PROJECT 2 (GRABOWSKI): ABSTRACT MR-based systems imaging of PD-related cognitive impairment and inherited variants in APOE or GBA. Emerging evidence indicates that variability in cognitive impairment in Parkinson Disease (PD) in part reflects fundamental biological heterogeneity. We hypothesize that the difference is mediated by differential compromise of intrinsic cortical systems, and that functional connectivity fMRI will demonstrate specific systems-level alternations in neurophysiologic relationships that vary depending upon the specific molecular driver of disease. The findings that APOE ?4 and GBA variants are robust genetic predictors of dementia in PD, and that they may modify the profile of the cognitive impairment, justify a focus on these genetically- defined groups. We will apply novel dynamic and established functional connectivity fMRI methods in APOE ?4 and GBA variant carriers, and healthy comparison subjects. These analyses will be conducted in the practical dopaminergic OFF state. We expect that APOE ?4 disproportionately affects memory-related systems including the parietal and temporal components of the default mode network, while GBA variants accelerate pathological effects on dopaminergic targets in the mesial frontal wall and the basal ganglia, and their functionally integrated lateral frontoparietal networks. Using the same genetically-defined participants, we will test the hypothesis that dynamic functional connectivity and network kernel analyses, approaches we have developed for both resting and task state fMRI, can sensitively predict the development and progression of cognitive impairment in PD. These analyses will be conducted with fMRI data taken ON dopaminergic medication. We will also evaluate whether functional connectivity predicting cognitive diagnosis and/or progression are invariant to dopaminergic replacement status. Finally we will investigate profiles of cortical systems change associated with biomarkers of different pathophysiologic mechanisms of cognitive impairment in PD. Our preliminary studies establish that omnibus and regional measures of system disruption increase in proportion to the (pathologic) reduction of ?-synuclein or A?42 concentration in CSF. We will replicate this finding in a separate group of PD participants and go on to analyze whether omnibus and regional measures of system disruption mediate the relationship between CSF biomarkers of cortical pathology and cognition. In secondary analyses informed by the other Projects in this Center, we will extend this novel approach to other markers of disease mechanisms: SAI (a measure of cholinergic tone, Project 3) and quantitative molecular pathology, Project 1. The new knowledge gained in this Project will be foundational to precision medicine for different molecular drivers of cognitive impairment in PD.